Deletion of Arginase 2 Ameliorates Retinal Neurodegeneration in a Mouse Model of Multiple Sclerosis
Optic neuritis is a major clinical feature of multiple sclerosis (MS) and can lead to temporary or permanent vision loss. Previous studies from our laboratory have demonstrated the critical involvement of arginase 2 (A2) in retinal neurodegeneration in models of ischemic retinopathy. The current study was undertaken to investigate the role of A2 in MS-mediated retinal neuronal damage and degeneration. Experimental autoimmune encephalomyelitis (EAE) was induced in wild-type (WT) and A2 knockout (A2−/−) mice. EAE-induced motor deficits, loss of retinal ganglion cells, retinal thinning, inflammatory signaling, and glial activation were studied in EAE-treated WT and A2−/− mice and their respective controls. Increased expression of A2 was observed in WT retinas in response to EAE induction. EAE-induced motor deficits were markedly reduced in A2−/− mice compared with WT controls. Retinal flat mount studies demonstrated a significant reduction in the number of RGCs in WT EAE retinas in comparison with normal control mice. A significant improvement in neuronal survival was evident in retinas of EAE-induced A2−/− mice compared with WT. RNA levels of the proinflammatory molecules CCL2, COX2, IL-1α, and IL-12α were significantly reduced in the A2−/− EAE retinas compared with WT EAE. EAE-induced activation of glia (microglia and Müller cells) was markedly reduced in A2−/− retinas compared with WT. Western blot analyses showed increased levels of phospho-ERK1/2 and reduced levels of phospho-BAD in the WT EAE retina, while these changes were prevented in A2−/− mice. In conclusion, our studies establish EAE as an excellent model to study MS-mediated retinal neuronal damage and suggest the potential value of targeting A2 as a therapy to prevent MS-mediated retinal neuronal injury.
KeywordsArginase 2 Retina Optic neuritis Neurodegeneration EAE Retinal ganglion cells
Ganglion cell complex
Experimental autoimmune encephalomyelitis
Ganglion cell layer
Inner plexiform layer
Inner nuclear layer
Outer plexiform layer
Outer nuclear layer
Optical coherence tomography
Retinal ganglion cells
Retinal nerve fiber layer
CDP implemented the experiments, analyzed the data, prepared the figures, and edited the manuscript. AYF helped with experimental design, analyzed the data, prepared figures, and wrote the manuscript. FL performed experiments, analyzed the data, and prepared the figures. ZX induced the in vivo experimental model and helped with analyzing the data. EM helped with induction of the model and clinical scoring. SG helped with experimental design and establishing the animal model in our laboratory. SBS provided assistance with SD-OCT experiment and edited the manuscript. RBC contributed to experimental design and revised the manuscript. SPN conceived, designed and coordinated the experiments, and finalized the manuscript.
This study was supported in part by the National Multiple Sclerosis Society (PP-1606-08778 to S.P.N.), National Eye Institute (R01EY028569 to S.P.N.), and Augusta University Culver Vision Discovery Institute.
Compliance with Ethical Standards
Conflict of Interest
The authors declare that they have no conflict of interest.
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